Contributions
Abstract: P1870
Type: Poster
Abstract Category: Late breaking news
The application of next generation sequencing technologies has proven very successful for the identification of pathogenic mutations for familial forms of complex diseases. In multiple sclerosis (MS), these approaches have led to the identification of mutations in NR1H3, CYP27A1, P2RX4/P2RX7 and NLRP1. Herein we describe the characterization of Canadian multi-incident MS families nominating pathogenic mutations in five additional genes.
Exome analysis identified a highly conserved NCOA3 arginine to cysteine substitution in eight patients from three unrelated families. Similarly, thirteen patients from seven ancestrally related families were found to harbor a valine to methionine substitution in CIDEA. Carriers of the NCOA3 or CIDEA mutation presented an average age at onset of disease of 28 years, and a disease course predominantly consistent with primary progressive MS, similar to the phenotype observed for NR1H3 and CYP27A1 mutation carriers. Interestingly, these four genes are components of nuclear receptor complexes or regulate the synthesis of oxysterols, which activate NR1H3 nuclear receptor complexes, thus nominating these pathways as key biological processes in progressive MS.
We also identified two mutations in NLRP12 in eight patients from two families. These mutations led to the substitution of two highly conserved leucine residues located in critical protein domains. The study of another family identified a mutation in complement C2 causing a threonine to methionine substitution. This mutation, which is evolutionarily conserved, was observed in four family members diagnosed with MS. Similarly, four siblings diagnosed with MS were found to harbor a PLAU mutation resulting in a cysteine to phenylalanine substitution. The mutated cysteine is a critical residue for the formation of a disulfide bond creating a kringle domain important for protein interactions. Patients identified with mutations in NLRP12, C2 or PLAU typically present relapsing remitting disease course at the onset of disease, a clinical phenotype similar to that observed for P2RX4-P2RX7 mutation carriers. The function of these genes is tightly linked and activate biological processes leading to an inflammatory response. Thus the identified mutations nominate the complement and coagulation cascades that activate purinergic receptors, triggering inflammasome formation causing the release of activated cytokines, as important biological pathways in relapsing remitting MS.
Disclosure: All authors: nothing to disclose
Abstract: P1870
Type: Poster
Abstract Category: Late breaking news
The application of next generation sequencing technologies has proven very successful for the identification of pathogenic mutations for familial forms of complex diseases. In multiple sclerosis (MS), these approaches have led to the identification of mutations in NR1H3, CYP27A1, P2RX4/P2RX7 and NLRP1. Herein we describe the characterization of Canadian multi-incident MS families nominating pathogenic mutations in five additional genes.
Exome analysis identified a highly conserved NCOA3 arginine to cysteine substitution in eight patients from three unrelated families. Similarly, thirteen patients from seven ancestrally related families were found to harbor a valine to methionine substitution in CIDEA. Carriers of the NCOA3 or CIDEA mutation presented an average age at onset of disease of 28 years, and a disease course predominantly consistent with primary progressive MS, similar to the phenotype observed for NR1H3 and CYP27A1 mutation carriers. Interestingly, these four genes are components of nuclear receptor complexes or regulate the synthesis of oxysterols, which activate NR1H3 nuclear receptor complexes, thus nominating these pathways as key biological processes in progressive MS.
We also identified two mutations in NLRP12 in eight patients from two families. These mutations led to the substitution of two highly conserved leucine residues located in critical protein domains. The study of another family identified a mutation in complement C2 causing a threonine to methionine substitution. This mutation, which is evolutionarily conserved, was observed in four family members diagnosed with MS. Similarly, four siblings diagnosed with MS were found to harbor a PLAU mutation resulting in a cysteine to phenylalanine substitution. The mutated cysteine is a critical residue for the formation of a disulfide bond creating a kringle domain important for protein interactions. Patients identified with mutations in NLRP12, C2 or PLAU typically present relapsing remitting disease course at the onset of disease, a clinical phenotype similar to that observed for P2RX4-P2RX7 mutation carriers. The function of these genes is tightly linked and activate biological processes leading to an inflammatory response. Thus the identified mutations nominate the complement and coagulation cascades that activate purinergic receptors, triggering inflammasome formation causing the release of activated cytokines, as important biological pathways in relapsing remitting MS.
Disclosure: All authors: nothing to disclose